Antiresorptives such as bisphosphonates (BP) and denosumab are commonly used osteoporosis treatments that are effective in preventing osteoporotic fractures by suppressing bone turnover. Although these treatments reduce fracture risk, their long-term use has been associated with atypical femoral fracture (AFF), a rare potential side effect. Despite its rare occurrence, AFF has had a disproportionately significant adverse impact on society due to its severe outcomes such as loss of function and delayed healing. These severe outcomes have led to the decrease in the use and prescription of osteoporosis treatment drugs due to patient anxiety and clinician reluctance. This creates the risk for increasing osteoporotic fracture rates in the population. The existing information on the pathogenesis of AFF primarily relies on retrospective observational studies. However, these studies do not explain the underlying mechanisms that contribute to AFF, and therefore the mechanistic origins of AFF are still poorly understood. The purpose of this review is to outline the current state of knowledge of the mechanical mechanisms of AFF. The review focuses on three major potential mechanical mechanisms of AFF based on the current literature which are (1) macroscale femoral geometry which influences the stress/strain distribution in the femur under loading; (2) bone matrix composition, potentially altered by long-term remodeling suppression by BPs, which directly influences the material properties of bone and its mechanical behavior; and (3) microstructure, potentially altered by long-term remodeling suppression by BPs, which impacts fracture resistance through interaction with crack propagation. In addition, this review presents the critical knowledge gaps in understanding AFF and also discusses approaches to closing the knowledge gap in understanding the underlying mechanisms of AFF.

抗骨吸收药物如双膦酸盐 (BP) 和狄诺塞麦是常用的骨质疏松症治疗方法，可通过抑制骨转换有效预防骨质疏松性骨折。尽管这些治疗降低了骨折风险，但长期使用会导致非典型股骨骨折 (AFF)，这是一种罕见的潜在副作用。尽管这种情况很少发生，但 AFF 因其功能丧失和愈合延迟等严重后果而对社会产生了不成比例的重大不利影响。由于患者的焦虑和临床医生的不情愿，这些严重的结果导致骨质疏松症治疗药物的使用和处方减少。这会增加人群中骨质疏松性骨折率的风险。AFF 发病机制的现有信息主要依赖于回顾性观察研究。然而，这些研究并没有解释导致 AFF 的潜在机制，因此 AFF 的机制起源仍然知之甚少。本综述的目的是概述 AFF 机械机制的当前知识状态。基于当前文献，综述重点关注 AFF 的三个主要潜在机械机制，它们是 (1) 宏观股骨几何形状，其影响负载下股骨的应力/应变分布；(2) 骨基质成分，可能被 BPs 的长期重塑抑制所改变，直接影响骨的材料特性及其力学行为；(3) 微观结构，BPs 的长期重塑抑制可能会改变，这通过与裂纹扩展的相互作用影响断裂阻力。此外，本综述提出了理解 AFF 的关键知识差距，并讨论了缩小理解 AFF 潜在机制的知识差距的方法。